This proposal details a comprehensive five-year training program for mentored career development in metabolomics applied to pulmonary arterial hypertension (PAH). In this proposal, the applicant seeks to integrate liquid chromatography tandem mass spectrometry (LC-MS/MS) based metabolite profiling with animal, cell and molecular biology techniques to investigate novel pathways in PAH pathogenesis. Candidate: The applicant is completing her pulmonary and critical care fellowship training in the Harvard Combined Program and will be joining the Massachusetts General Hospital (MGH) as junior faculty upon graduation. The applicant has proposed a research program specifically constructed to provide additional training that will serve as the foundation for her transition towards an independent career as a PAH bench investigator with expertise in metabolomics. Environment: A joint mentorship between Dr. Robert Gerszten, a cardiologist with nationally recognized expertise in metabolomics, and Dr. Benjamin Medoff, Pulmonary Division Chief at MGH and pulmonary biology expert, has been established to foster the applicant's scientific and career development. The supportive scientific advisory committee includes Dr. Clary Clish, Director of Metabolite Profiling at the Broad Institute and Dr. Kenneth Bloch, a renowned cardiologist and pulmonary vascular biologist. Research: This proposal builds on preliminary studies that have identified a novel association of metabolites in the kynurenine pathway with PAH. This pathway is a major route for tryptophan metabolism catalyzed by the enzyme, indoleamine 2,3-dioxygenase 1 (IDO1) and has been implicated in the regulation of vascular tone. We will test the hypothesis that the kynurenine pathway leads to a compensatory pulmonary vasodilation in PAH. In Aim 1, we will characterize IDO1 and kynurenine pathway metabolites in the lungs of mice in a well-established murine model of PAH induced by chronic hypoxia. In Aim 2, we will examine the functional effects of IDO1 deficiency on the development of PAH in vivo. Furthermore, metabolite profiling will allow a broader view of the role of this pathway in the cell-based and animal systems described in this proposal. Public Health Relevance: espite advances in the diagnosis and treatment of PAH, the annual mortality rate remains unacceptably high. PAH remains a therapeutic challenge since our fundamental understanding remains limited. This proposal aims to identify the changes in metabolic pathways and investigate underlying mechanisms in PAH. By highlighting novel pathways, this research may ultimately lead to new targets for PAH therapy. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and cellular hyperproliferation leading to increased pulmonary vascular resistance and progressive right heart failure. PAH remains a therapeutic challenge since our fundamental understanding remains limited. The goal of this proposal is to identify new pathways in PAH pathogenesis using metabolite profiling and to elucidate functional significance of these novel pathways by integrating animal, cell and molecular biology techniques.